The invention relates to treatment planning for neutron capture therapy.
Neutron Capture Therapy (NCT) was "born" in 1936, soon after the 1932 discovery of the neutron by Chadwick. Gordon Locher, a biophysicist at Strathmore College, proposed the principle of boron-neutron capture therapy as a potential future method of treating cancer. Boron-10, a naturally occurring isotope of boron, had been known since the 1934 work of Goldhaber in Cambridge, England to have an unusually high avidity for capturing slow ("thermal") neutrons. Immediately after capturing a slow neutron, .sup.10 B was found to disintegrate into an energetic alpha particle and a recoiling .sup.7 Li ion, with a combined range in water of about 12-13 microns. Locher proposed, with impressive foresight, that if boron could be selectively concentrated in a patient's tumor and the area then flooded with slow neutrons, a higher radiation dose to tumor would result, thereby killing the tumor.
In 1940, Kruger at the University of Illinois reported on the reduced viability of transplanted mouse tumors following their exposure to boric acid paste and irradiation with slow neutrons. Zahl also reported the regression of mouse sarcomas in vivo after their infiltration with boric acid paste.
It was realized, even in those early years, that because of the poor penetration of slow neutrons in tissue NCT would be difficult to apply to the treatment of deeply-seated tumors in humans. In 1941, Zahl suggested that to overcome this potential problem, neutrons of higher energy would need to be used; these "epithermal" neutrons would not be captured by .sup.10 B until they had slowed down to thermal energies at a few centimeters depth in tissue. Today, the only two available clinical neutron beams designed for NCT are at MIT and BNL and are, indeed, epithermal beams.
In 1950/51 William Sweet, at Massachusetts General Hospital, Boston, and Lee Farr at Brookhaven National Laboratories (BNL), Long Island, N.Y. both proposed initiation of clinical studies of NCT using the newly commissioned Brookhaven Graphite Research Reactor (BGRR). In 1951, a clinical thermal neutron beam became available at the BGRR, and over the following two years ten patients with high-grade brain tumors were treated by NCT by Farr and Sweet. The form of the boron used was .sup.10 B-enriched borax, administered to the patients intravenously shortly prior to neutron irradiation. These patients were highly advanced cases, in most cases already pre-irradiated by conventional radiotherapy, and not selected to exclude deeply-seated tumors. No observable benefit was derived from this first series of NCT patients, neither was there any serious radiation damage to normal tissues. However, because the borax was found to be somewhat toxic, a different boron compound, sodium pentaborate, was used in the next series of nine high-grade brain tumor patients.
An unexpected new problem arose with this second series of BNL patients, probably related to the higher circulating blood concentrations of the sodium pentaborate compound. These patients exhibited quite severe radiation injuries to the scalp and superficial normal brain. In a third series of patients treated by NCT at the BGRR, the pentaborate boron compound was delivered into the internal carotid artery in order to try to minimize the blood boron levels, and the total neutron fluence delivered was reduced. In these patients severe scalp injuries were avoided, but as with the previous patients no significant benefit of the NCT was evident.
During 1959-1961, a third series of seventeen high-grade brain tumor patients was treated by NCT at BNL at the newly commissioned Brookhaven Medical Research Reactor (BMRR). No observable benefit in terms of increased survival accrued to these patients, with the possible exception of one. In this patient, who subsequently died of distance metastases, pathology on the brain showed no viable tumor present, thus suggesting that a local cure might have been achieved. This appears to be the only definitive evidence of successful NCT in humans from the early clinical trials.
During the same 1959-1961 period, William Sweet with the help of a physicist Gordon Brownell treated seventeen high-grade brain tumor patients with the clinical thermal neutron beam at the recently commissioned MIT Research Reactor, MITR-I, using a different boron compound, p-carboxybenzene boronic acid, intravenously administered. This compound was developed by a chemist at the Massachusetts General Hospital, Albert Soloway. Two further patients were treated by NCT using yet another compound developed by Soloway, sodium perhydrodecaborate. This latter compound appeared to be less toxic and contained a higher weight fraction of boron than the earlier compounds. Unlike the upward facing beam of the BGRR or the horizontal beam of the BMRR, the MITR-I beam was downward facing, emerging from the ceiling of a specially constructed treatment room beneath the reactor. This enabled Sweet to surgically reflect the scalp, skull, and dura, and to resect any gross tumor immediately prior to irradiation. The patients were then intraoperatively treated through an open craniotomy. Treatment of the patients in this fashion was facilitated by the orientation of the MITR-I neutron beam. This maneuver theoretically increased the depth to which the therapy could be effective, mimicking in a sense the anticipated effect of the epithermal neutron beam proposed in the 1940's by Kruger. Once again, although scalp injuries were avoided, some normal brain injuries resulted and no discernable benefit in terms of extended lifespan accrued.
Because of the discouraging results of the four patient series at BNL and MIT, clinical NCT in the U.S. was abandoned. Despite these setbacks for NCT, two research groups, at Massachusetts General Hospital/MIT under the direction of William Sweet and Gordon Brownell, and at BNL under the direction of Ralph Fairchild, continued to study NCT from the perspective of developing improved boronated compounds, improved neutron beams (initially improving the quality of the thermal beams, and later developing epithermal beams), and analytic methods for the measurement of boron concentrations in tissues and in blood. Deficits in the following three areas, it is now believed, were primarily responsible for the earlier failures of NCT: the lack of boron compounds exhibiting high tumor/blood partition; the poor tissue penetrability of the existing thermal neutron beams--even with intraoperative treatment; and the lack of "on-line" analytic methods to assay the blood and tissue boron concentrations close to the time of neutron irradiation.
Monte Carlo-based treatment planning techniques for neutron capture therapy have been developed in support of the New England Medical Center/Massachusetts Institute of Technology program in neutron capture therapy (NCT). These techniques enable dose distributions to be displayed as easily understandable isocontours superimposed on precisely corresponding CT or MRI diagnostic images of the animal or human body part being irradiated. This provides the radiation oncologist with a display of the doses received both by the tumor and by various normal tissues. Furthermore, in those patients who do not survive it provides the opportunity to retrospectively perform accurate dosimetric/pathological correlations leading to improved understanding of the clinical response to NCT. The details of this approach are presented and a typical treatment plan involving the parallel-opposed epithermal neutron irradiation of a patient with a glioblastoma multiforme is presented.
Accurate treatment planning for NCT, as for any form of experimental radiation therapy, is beneficial not only for the safety and optimal management of the patient but also for providing correlated radiological/pathological information in those patients who ultimately fail the experimental therapy. This allows the dose-response properties of a new radiation modality to be better understood. Computer-aided treatment planning approaches specifically for NCT of human subjects have previously been reported. See, for example, references 1-4 in the table of references identified as Table A at the end of the specification. (Note that all subsequent references to related articles appear in parentheses and identify the number of the reference in Table A. All of the references listed Table A are incorporated herein by reference.)